HIV-infected individuals have improved survival in the highly active antiretroviral therapy (HAART) era, but continue to have a higher risk of mortality from other serious illnesses such as squamous cell cancer of the anus (SCCA) and other non-AIDS defining malignancies. Because SCCA precursor lesions are readily identifiable using cytologic screening, SCCA may be a preventable cause of death among HIV-infected individuals. SCCA shares many biologic similarities with the AIDS-defining malignancy cervical cancer, including a causal relationship with high-risk human papillomavirus (HPV) infection and an increased incidence of both cancers in HIV-infected populations. Past research and preliminary data indicate that the incidence of SCCA is increasing in spite of HAART utilization, and that the effect of HAART on anal cancer precursor lesions is unclear. The relative influence of HAART use compared to other possibly confounding factors including length of HIV infection, nadir CD4 count, and HPV-related factors are unknown. The goals of this proposal are to assess the changes in the incidence of SCCA since the wide-spread introduction of HAART and identify relevant factors responsible for those changes. The specific aims for this proposal are: 1) To test the hypothesis that prolonged, advanced immunosuppression is associated with the development of SCCA;2) To test the hypothesis that the prevalences of anal dysplasia, and high-risk HPV infection in a HAART naive, demographically understudied population is increased, and to determine if high-risk HPV viral load is independently associated with grade of anal dysplasia and advanced immunosuppression;3) To measure the relative effect of baseline immunosuppression, and subsequent immunologic response to HAART initiation on the progression to high-grade anal dysplasia and high-risk HPV viral loads. The first specific aim will be accomplished with a retrospective cohort study using a unique, national, Veteran's Health Administration HIV registry. The 2nd aim will be addressed through a cross-sectional study evaluating a HAART-naive HIV-infected cohort and the 3rd aim will be accomplished by prospectively following the members of that cohort. The research plan, didactic training and outstanding mentoring environment, will allow the principal investigator to acquire new skills as well as refine existing skills in the development and execution of clinical studies, allowing her to develop into an independent investigator in the epidemiology, prevention and care of HIV-related malignancies.